19-homo-steroids

ABSTRACT

THE INVENTION COMPRISES 19-HOMO-STEROIDS OF THE FORMULA   17-R2,17-R3,19-R1-ESTRANE WITH R IN PLACE OF #3 CH2   HAVING UNSATURATED A AND/OR B RINGS, WHEREIN R IS A KETO, ALKOXY, HYDROXY OR ACYLOXY; R1 IS LOWER ALKYL HAVING AT LEAST 2 CARBON ATOMS OR LOWER ALKEN-1&#39;&#39;-YL; R2 IS HALOLOWER-ALKENYL OR HALO-LOWER-ALKYNYL; AND R3 IS HYDROXY, ACYLOXY OR ALKOXY WHICH COMPOUNDS ARE USEFUL AS ANTIGONADOTROPHIC AGENTS.

United States Patent 015cc Int. Cl. C07c 169/20 US. Cl. 260-397.4 25Claims ABSTRACT OF THE DISCLOSURE The invention comprises19-homo-steroids of the formula having unsaturated A and/or B rings,wherein R is a keto, alkoxy, hydroxy or acyloxy; vR is lower alkylhaving at least 2 carbon atoms or lower alken-1-yl; R ishalolower-alkenyl or halo-lower-alkynyl; and R is hydroxy, acyloxy oralkoxy which compounds are useful as antigonadotrophic agents.

Formula I This invention relaes to 19-homo-steroids of FOrmula I whichcompounds are useful as antigonadotrophic agents.

The 19-homo-steroids of Formula I are represented by the formula A Ln Qt Formula I wherein R is selected from the group consisting of a 3-keto-A, 3-keto-A 3-ketoA 3keto-A 3-alkoxy- A 3-alkoxy-A 3-alkoxy-A3-alkoxy-A 3-hydroxy A 3-hydroxy-A 3-acyloxy-A 3-acyloxy-A 3- acyloxy-A,3-acy1oXy-A system; R is selected from the group consisting of loweralkyl having at least two carbon atoms and 'loWer-alken-l'-yl; R isselected from the group consisting of halo-lower-alkenyl andhalo-loweralkynyl; and R is selected from the group consisting ofhydroxy, acyloxy and alkoxy.

Where R in Formula I represents lower-alkyl, the representative alkylgroup can be either straight-chained or branch-chained containinganywhere from two to eight carbon atoms, e.g. ethyl, N-propyl,isopropyl, butyl, isomers thereof and the like. As noted, R in Formula Ican also represent a lower alken-1-yl group in which case the group canlikewise be either straight-chained or branch-chained containing up toeight carbon atoms. For example, the lower-alken-1'-yl group can bevinyl, buten- 1'-yl, propen-1-yl, isomers thereof and the like. In apreferred embodiment, R will represent ethyl or propen- 1'-yl.

The term halo as used herein, comprehends all of the halogens, namely,fluoro, chloro, bromo and iodo. In a preferred embodiment, halo willrepresent fluoro or 3,642,839 Patented Feb. 15, 1972 chloro.Lower-alkenyl and loWer-alkynyl each comprehend groups having up toeight carbon atoms. Where R represents halo-lower-alkenyl, therepresentative loweralkenyl group can, for example, be vinyl, allyl,methallyl, propen-1'-yl and the like; these groups can, in turn, besubstituted by at least one halogen atom (e.g. trifluorovinyl,trifluoropropenyl, dichlorovinyl, dibromovinyl, etc.). Where Rrepresents halo-lower-alkynyl, such groups can, for example, bechloroethynyl, bromoethynyl, trifluoropropynyl, iodoethynyl,chlorobutynyl and the like. In a preferred embodiment, R will representtrifluoropropynyl.

Suitably R and R in Formula I each represent an acyloxy group containingthe residue of a saturated aliphatic, unsaturated aliphatic or aromaticcarboxylic acid either of which contain up to 10 carbon atoms, e.g.,acetic acid, propionic acid, caproic acid, pivalic acid, butyric acid,valeric acid, benzoic acid and the like. Preferably, the acyloxy groupcontains the residue of acetic acid. Furthermore, R and R can also eachsuitably represent an alkoxy group containing anywhere from one to eightcarbon atoms, e.g., methoxy, ethoxy, propoxy, butoxy, pyranyloxy,isomers thereof and the like. A preferred embodiment utilizes methoxy ortetrahydropyranyloxy.

The l9-horno steroids of Formula I can be produced by a variety ofmethods. Firstly, the 19-homo-steroids of Formula I can be produced byreacting a compound of Formula II wherein R is as above defined; and Ris selected from the group consisting of a 3-enamino-A 3-alkoxy-A3-alkoxy-A 3-alkoXy-A 3-alkoxy-A 3-acyloxy-A 3-acyloxy-A 3-acyloXy-A ora la-acyloxy-A system, with a Grignard reagent of the formula R MgY oran alk-lithium compound of the formula R Li, wherein R" is as abovedefined and Y is a fluorine, chlorine, bromine or iodine atom; and ifdesired, hydrolyzing the resulting product produced therefrom.

The above reaction, which uses a Grignard reagent or an alk-lithiumcompound, effects the conversion of the 17-oxo group of Formula II to atertiary alcohol group. The optional if desired step, comprisinghydrolysis of the resulting product, is required for production of a3-keto group where the compound of Formula II contains a 3-alkoxy,3-enamino or 3-acyloxy group at C3, i.e. the position represented by RConversion of the 17-oXo group of a compound of Formula II into atertiary alcohol group can be effected according to conventionaltechniques using, for example, the Grignard reagent or an alk-lithiumcompound described herein. The reaction which converts a compound ofFormula II to a compound of Formula I is suitably conducted in thepresence of an ether solvent (e.g. diethyl ether, tetrahydrofuran,dioxane, etc.). The hydrolysis of the 3-enamino, 3-enol ether or 3-enolester group of the resulting product is suitably accomplished using anacid (e.g. acetic, dil. hydrochloric, etc.) to produce a compound ofFormula I having a 3-keto-A or S-keto-A system.

Grignard reagents of the formula R MgY (wherein R and Y are as abovedescribed) can be prepared in a conventional manner using an alkylmagnesium halide Formula II (e.g. ethyl magnesium bromide) and ahaloalkynyl or haloalkenyl compound. Alk-lithium compounds can beprepared in a conventional manner reacting an alkyllithium compound(e.g. methyl lithium, butyl lithium, etc.) with a halo-alkynyl orhalo-alkenyl compound such as chloroacetylene, trifiuoropropyne,dichloroethylene, dibromoethylene and the like. Either of thesealk-lithium compounds can be reacted in situ with a steroid of FormulaII.

Alternately, the l9-homo-steroids of Formula I can be prepared bydehydrogenating a compound of Formula III Formula III in the 1(2) and/or6(7) position. A 1(2)-dehydrogenation can be effected using seleniumdioxide in amyl alcohol or with a benzoquinone (e.g.dichlorodicyanobenzoquinone) in benzene or in dioxane containing a smallamount (about 0.1-1%) of a mineral acid. Similarly, a6(7)-dehydrogenation can be effected using a benzoquinone or chloranilin dioxane containing about 1 to of a mineral acid. The introduction ofa double bond at the 6(7) position can also be effected by reacting acompound of Formula I, having a 3-alkoxy-A system, withdichlorodicyanobenzoquinone in water containing an organic solvent suchas 95% acetone or dioxane.

Thirdly, the 19-homo-steroids of Formula I can be prepared byenol-esterifying or enol-etherifying a compound of Formula III or a6(7)-dehydro derivative thereof. For example, a compound of Formula III(or a 6(7) dehydro derivative thereof) can be reacted with an acylatingagent (e.g. isopropenyl acetate) in the presence of a catalyst (e.g.toluene-sulfonic acid) to produce l9-homosteroids of Formula I having a3-acyloxy-A or 3- acyloxy-A system.

A fourth procedure for preparing the l9-homo-steroids of Formula Icomprises acylating or alkylating a 19- homo-steroid of Formula I havinga free hydroxy group at 0-3 or C-17. The acylation of a free hydroxygroup at C-3 or C-17 can be effected using a reactive acyl derivativesuch as an acyl anhydride or halide in the presence of a base likepyridine.

Alkylation of an unprotected hydroxy group at C3 can be effected byreacting a steroid of Formula I with an alcohol containing theparticular alkyl group to be introduced or with a dialkoxypropane (e.g.2,2-dimethoxypropane) in methanol/dimethyl formamide. The reaction byeither of the two methods suitably proceeds in the presence of acatalyst such as p-toluenesulfonic acid. The alkylation at C-3 can alsobe effected using an orthoformic acid ester in the presence of an acid(e.g. hydrochloric acid).

Alkylation of an unprotected hydroxy group at C-l7 can be effected byconverting the steroid of Formula I into its corresponding metal salt.This conversion is accomplished by first reacting the steroid with, forexample, sodium or lithium amide and then secondly with an alkyl iodide.This two-step reaction protects the optionally present keto group at C3by its formation of a ketal or enolether. For example, reacting asteroid of Formula I, having a hydroxy at C-3, with dihydropyran in thepresence of p-toluenesulfonic acid produces a tetrahydropyranyl ether.

Fifthly, the compounds of Formula I, wherein R is a 3-keto A or 3-keto-Asystem can be prepared by reducing a keto group to a hydroxy group atC-3 in a l9-homosteroid of Formula I, to a hydroxy group. The reductioncan be effected with reducing agents such as complex metal hydrides;preferably, lithium aluminum hydride or sodium borohydride is utilized.

A further and sixth process for producing the l9-homosteroids of FormulaI comprises reacting a compound of Formula IV Formula lV wherein R is asabove defined, and R is selected from the group consisting of acyloxyand alkoxy, with a strong base and treating the resulting metal saltwith a reagent which yields a positive halogen atom(s). Suitable strongbases for preparing the metal salt, are for example, lithium amide,sodium amide and the like. Reagents comprehended as yielding a positivehalogen atoms(s) are, for example, chlorine, bromine, N-chloro-orN-bromo-amides (e.g. N-chloro-or), N-bromo-amides (e.g.N-chlorosuccinimed), trifluorobromomethane-hept fluoro-l-iodo-propaneand the like.

An alternate and seventh process for preparing the 19- homo-steroids ofFormula 1 comprises reacting a compound of Formula V Formula V whereinR, R and R are each as above defined, and R is di-halo (lower alkenyl),with a strong base so to splitoff a hydrogen halide from said steroid ofFormula V. As applied to this process, the term strong base comprehendsthat base which can split-off a hydrogen halide from a dihaloalkenylside-chain of a compound of Formula V with the resultant formation of ahaloalkynyl grouping; for example, potassium tert-butylate,trimethylbenzylammonium hydroxide and the like.

The last of nine processes for preparing the 19-homosteroids of FormulaI comprises hydrogenating the halolower-alkynyl group of a compound ofFormula VI Formu a VI in the following procedure: 21-day old male ratswere each administered 4 mg. a 19-homo-steroid of Formula Isubcutaneously for 6 days. The weights of the testicles and ventralprostates of each animal were subsequently compared to the weightsobtained from untreated control animals. The relative decrease in weightof the organs of the treated animals represents a measure of theantigonadotropic activity of the steroids administered. The valuesobtained for specific 19-homo-steroids are expressed as a percentage andare set-forth in Table I. The mean value of the organ Weights, as apercentage, was calculated using the following formula whereinrepresents the mean value of the weight of the organs of the animals.

73 Treated Animals "X Untreated Animals The 19-homo-steroids of FormulaI evidence therapeutic usefulness as compounds and can be used in manypharmaceutical preparations. For example, the compounds can be combinedwith many pharmaceutically acceptable inert carriers to preparepharmaceutical preparations suitable for enteral, percutaneous and/ orparenteral applications. As used herein, pharmaceutically acceptableinert carriers comprehend organic and inorganic materials such as water,gelatin, gum arabic, lactose, starches, magnesiurn stearate, talc,vegetable oils, polyalkyleneglycols, petroleum jelly, and the like.These pharmaceutical preparations can also contain other therapeuticallyvaluable substances, and can be in several forms such as solid form(e.g. tablets, dragees, suppositories, capsules, etc.); semisolid form(e.g. ointments, creams, etc.); or in liquid form (e.g. solutions,suspensions, emulsions, etc.). Each pharmaceutical preparation can besterilized and/or contain additives such as preservatives, stabilizers,wetting or emulsifying agents, buffering salts and osmotic pressurevarying salts. The amount of compound of Formula I administered shouldbe adjusted by the individual administering it to suit the particularsituation. The following examples are given to illustrate the invention.

TABLE I Administered 19-homo-steroid of Formula I19-methylene-21-ehloro-17-hydroxy-17a-pregna- .100=Percent (70)Testieles Prostate 1,4-dien-20yn3-one G 3219-methylene-21-chloro-17-hydroxy-17a-pregna- 4,6-dien-20-yu-3-one 50 38CIsIQ-ethylidene-21-ehloro-l7-hydroxy-17a-pregn- 56 34Trans-19-ethylidene-21-chloro pregn-4en-2(%yn-3-one 44 33Cis-lQ-ethylidene-21-ehloro-17-hydroxy-17apregna-4,6-dien-20-yn-3-one 4829 Cis-19 ethylidene-17B-hydroxy-16(tr1fiuoro-1- propynyl)-andorst-4en3'one 58 40 1Q-ethyl21-chloro-17-hydroxy17a-pregna-l,4

dien-20-yn-3-one 49 42 EXAMPLE 1 Preparation of:19-ethyl-21-chloro-17-hydroxy-17apregn-4-en-20-yn-3-one 50 ml. of2,2-dimethoxypropane, 2 ml. of methanol and 260 mg. ofp-toluenesulphonic acid are added to a solution of g. of19-ethylandrost-4-ene-3,17-dione in 50 ml. of dimethylformamide. Thereaction mixture is boiled at reflux for 2 hours under an argonatmosphere. After cooling, the reaction mixture is reacted with 2 g. ofsodium bicarbonate and then poured into a large amount of water andextracted with ether that contains a small amount of pyridine. Theethereal extract is thereupon washed twice with water and dried overanhydrous potassium carbonate. Evaporation from ethanol yielded: 19-ethyl-3-methoxyandrosta-3,5-dien-17-one.

A solution of 6.15 g. of cis-dichloroethylene in 40 ml. of ether isadded dropwise to 61 ml. of a 1.68 N solution of methyl-lithium over aperiod of one hour at 0 C. and under an argon atmosphere. The reactionmixture is then stirred at room temperature for two hours, and asolution of 2.16 g. of 19-ethyl-3-methoxy-androsta-3,S-dien- 17-one in50 ml. of ether is thereafter added dropwise.

The resulting reaction mixture is stirred at room temperature for anadditional 2 hour period, cooled to 0 C. and reacted with a 50 ml.solution of saturated ammonium chloride. The reaction mixture is thenextracted with ether, the ethereal phase washed with a saturated sodiumchloride solution, dried over sodium sulphate and evaporated. Theresidue is thereupon dissolved in 40 ml. of dioxane, reacted with amixture of 2 ml. of conc. hydrochloric acid and 2 ml. of water andstirred at room temperature under an argon atmosphere for 2 hours. Thesolution is thereafter poured into ice-water and extracted with ether.Chromatography of the product on silica gel with hexane/ ether (1:1)yielded: 19-ethyl-21-chloro-17-hydroxy-l7apregn-4-en-20-yn-3-one. M.P.162-164.

EXAMPLE 2 Preparation of: cis-l9-ethylidene-21-chloro-17-hydroxy- 17a-pregn-4-en-20-yn-3-one Using the procedure secondly described inExample 1, cis-l9-ethylidene 3 meth0xyandrosta-3,S-dien-17-one (M.P. 118C.) was prepared from 2,2-dimethoxypropane, methanol, p-toluenesulfonicacid and cis-19-ethylideneandrost-4-one-3,17-dione.

Using the procedure first described in Example 1, cisl9-ethylidene 21chloro-l7-hydroxy-17a-pregn-4-en-20- yn-3-one was prepared fromcis-dichloroethylene in ether, methyl-lithium andcis-l9-ethylidene-3-methoxyandrosta- 3,5-dien-17-one. M.P. 165-166 C.(crystallized from methylene chloride/ ether). UV: \e =13,9O0; [a] +26(c.=0.1 in dioxane).

EXAMPLE 3 Preparation of: trans-l9-ethylidene-2l-chloro-17-hydroxy-17a-pregn-4-en-20-yn-3-one 10 g. ofcis-19-ethylideneandrost-4-ene-3,17-dione is boiled at reflux for 4hours with 5 g. of anhydrous sodium acetate, 2 g. of 5%palladium-charcoal in 150 ml. of abs. ethanol and a 1% solution ofcyclohexene in ethanol. The cyclohexene solution is added dropwise atthe rate of 40 ml. per hour. The reaction mixture is then cooled andfiltered, the filtrate of which is further reacted with ml. of water andevaporated to a volume of about 200 ml. and then, at the boilingtemperature, reacted with water until the mixture is slightly turbid.Cooling yielded crystalline trans-l9-ethylideneandrost-4-ene-3,17-dioneM.P. 174-175" C. (from methylene chloride/ ether). UV: 62: :15,400;[0L]589==+219 (C.'=0.1 in dioxane).

Usin the procedure secondly described in Example 1,trans-19-ethylidene-3-methoxyandrosta-3,S-dien 17 one wasprepared from2,2 dimethoxypropane, methanol, p-toluenesulfonic acid andtrans-l9-ethylideneandrost-4- ene-3,17-dione.

Using the procedure first described in Example 1,transl9-ethylidene-2l-chloro 17 hydroxy-17a-pregn-4-en-20 yn-3-one wasprepared from cis-dichloroethylene in ether, methyl-lithium and trans 19ethylidene-3-methoxyandrosta-3,5-dien-17-one. M.P. 162-164 C.(crystallized from ether/hexane). UV: e =15,950; [a] =+44 (c.=0.1 indioxane).

EXAMPLE 4 Preparation of: l9-rnethylene-21-chloro-l7-hydroxy- 17a-pregn-4-en-20-yn-3-one Using the procedure secondly described inExample 1, l9-methylene 3 methoxyandrosta-3,S-dien-l7-one was preparedfrom 2,2-dimethoxypropane, methanol-p-toluenesulfonic acid andl9-methyleneandrost-4-ene-3,17-dione.

Using the procedure first described in Example 1, l9-methylene-21-chloro17 hydroxy-17a-pregn-4-en-20- yn-3-one was prepared fromcis-dichloroethylene in ether, methyl-lithium and19-methylene-3-Inethoxyandrosta-3.5- dien 17-one. M.P. 133-134 C.(crystallized from ISO- propyl ether); UV: e =l6,000; [u] =+27 (c.=0.1in dioxane).

7 EXAMPLE 5 Preparation of: cis-19-ethylidene-17B-hydroxy-17-(trifluoro-l-propynyl) -androst-4-en-3-one A Grignard solution is effectedin the conventional manner i.e., from 2.43 g. magnesium and 10.9 g.ethyl bromide in 170 ml. of tetrahydrofuran in an argon atmosphere.

A solution of 18.8 g. of trifiuoropropyne in 100 ml. of tetrahydrofuranis added dropwise to the Grignard solution at C. and stirred at roomtemperature for 1 hour. A solution of 6.5 g. ofcis-19-ethylidene-3-methoxyandrosta-3,5-dien-17-one in 100 ml. oftetrahydrofuran is then added and the reaction mixture boiled at refluxfor 2 hours. After cooling to 0 C. the mixture is reacted with a 100 ml.solution of saturated ammonium chloride. The resulting reaction mixtureis thereafter extracted with methylene chloride, the extract washeduntil neutral, dried and the solvent evaporated. The enol-ether thusobtained is hydrolyzed in hydrochloric acid dioxane as first describedin Example 1. Chromatography on silica gel with hexane/acetone (9:1)yielded: cis-l9-ethylidene-17flhydroxy 17(trifiuoro-l-propynyl)-androst-4-en-3-one. M.P. 235 237 C. (crystallizedfrom ether-hexane). UV: e =15,0O0, [a] =+45 (c.=0.1 in dioxane).

EXAMPLE 6 Preparation of: cis-19-ethylidene-21-chloro-17-hydroxy-Hot-pregna-1,4-dien-20-yn-3-one A solution of 104 g. ofcis-l9-ethylidene-21-chloro- 17-hydroxy-l7a-pregn-4-en-20-yn-3-one in500 ml. of benzene is reacted with 7.35 g. ofdichlorodicyanobenzoquinone and boiled at reflux under an argonatmosphere for 48 hours. After cooling, the reaction mixture is filteredover 200 g. of aluminum oxide (activity II), and rinsed with aceticester. "Extraction and chromatography of the extract on a 100-foldquantity of silica gel with cyclohexane/acetic ester (4:1) yielded:cis-19-ethylidene-2lchloro-17-hydroxy-l7a-pregna-1,4-dien-20-yn-3-one.M.P. 233-234 C. (crystallized methylene chloride/ether); UV: e =15,OOO;[a] =-100 (c.=0.1 in dioxane).

EXAMPLE 7 Preparation of: trans-19-ethylidene-21-chloro-17-hydroxy-Nix-pregna-1,4-dien-20-yn-3-one Using the procedure described in Example6 trans-19- ethylidene-Zl-chloro 17 hydroxy-17u-pregna-1,4-dien-20-yn-3-one was prepared from dichlorodicyanobenzoquinone andtrans-19-ethylidene-2l-chloro-17-hydroxy- 17ot-pregn-4-en-20-yn-3-one inbenzene. M.P. 168-170 C. (crystallized from ether/hexane); UV: e=14,400; [G.] 9 ---'6]. (C.=0.1 in dioxane).

EXAMPLE 8 Preparation of: 19-rnethylene-21-chloro-17-hydroxy17a-pregna-1,4-dien-20-yn-3-one Using the procedure described in Example6, l9-methylene-Zl-chloro-l7-hydroxy-l7a-pregna 1,4 dien--yn- 3-one wasprepared from dichlorodicyanobenzoquinone and19-methylene-2l-chloro-17-hydroxy 17a pregn-4- en-20-yn-3-one inbenzene. M.P. 196197 C. (crystallized from acetone/hexane); UV: 6148,000; [a] 48 (c.=0.1 in dioxane).

EXAMPLE 9 Preparation of:19-ethyl-21-chloro-17-hydroxy-17apregna-1,4-dien-20-yn-3-one Using theprocedure described in Example 6, 19-ethyl- 2l-chlo1'o-17-hydroxy 170:pregna-l,4-dien-20-yn-3-one was prepared fromdichlorodicyanobenzoquinone and 19- ethyl-2l-chloro-17-hydroxy 17o:pregn-4-en-20-yn-3-one 8 in benzene. M.P. 202-203 C. (crystallized fromacetone/hexane); UV: e =15,4O0; [a] =43 (c.=0.1 in dioxane).

EXAMPLE 10 Preparation of:cis-19-ethylidene-17/8-hydroxy-17-(trifluoro-1-propynyl)-androsta-1,4-dien-3-oneUsing the procedure described in Example 6, cis-19- ethylidene-178-hydroxy-17-(trifluoro 1 propynyl)-androsta-1,4-dien-3-one was preparedfrom dichlorodicyanobenzoquinone and cis l9 ethylidene 17/3 hydroxy-17(trifluoro-l-propynyl)-androst-4-en-3-one-in benzene M.P. 2l82l9 C.(crystallized from ether/hexane); UV: (250 15,200; [0L]589: (C.=O.1 indioxane).

EXAMPLE 11 Preparation of: cis l9 ethylidene 21chloro-17-hydroxy-17a-pre-gna-4,6-dien-20-yn-3-one A solution of 3.6 g.of cis-19-ethylidene-21-chloro-17- hydroxy-17a-pregn-4-en-20-yn-3-one inml. of dioxane and containing 6.5% of hydrogen chloride is addeddropwise to a solution of 2.6 of dichlorodicyanobenzoquinone in 125 ml.of dioxane containing 6.5% of hydrogen chloride over a 3 minute periodand under an argon atmosphere. The mixture is stirred at roomtemperature for an additional 7 minutes whereupon 45 g. of solid sodiumbicarbonate is added in small portions. The mixture is then furtherstirred for 15 minutes, treated wtih 250 ml. of benzene and filtered.The filtrate is filtered over 70 g. of aluminum oxide (activity II), andrinsed with acetic ester. Evaporation of the extract and chromatographyon a 50-fold quantity of silica gel with hexane/acetone (9: 1) yielded:cis-l9-ethylidene 21 chloro-17-hydroxy-l7apregna 4,6 dien 20 yn-3-one.M.P. 144145 C.; UV e =22,600; [a] --22 (c.=0.1 in dioxane).

EXAMPLE 12 Preparation of:cis-l9-ethylidene-Uri-hydroxy-17-(trifluoro-l-propynyl)-androsta-4,6-dien-3-oneUsing the procedure described in Example 11, cis-l9-ethylidene-l7fl-hydroxy 17 (trifluoro l propynyl)-androsta-4,6-dien-3-one was prepared from dichlorodicyanobenzoquinone indioxane containing hydrogen chloride andcis-19-ethylidene-17,8-hydroxy-l7-(trifiuoro- 1-propynyl)-androst 4en-3-one in dioxane containing hydrogen chloride. M.P. 254256 C.; UV: e=24,600; [a] =20 (c.=0.1 in dioxane).

EXAMPLE 13 Preparation of: trans-l9-ethylidene-21-chloro-17-hydroxy-17ot-pregna-4,6-dien-20-yn-3-one Using the procedure described inExample 11, trans- 19ethylidene-Zl-chloro-17-hydr0xy-17a-pregna-4,6-dien- 20-yn-3-one wasprepared from dichlorodicyanobenzoquinone in dioxane containing hydrogenchloride and trans-l9-ethylidene 21 ch1oro-17-hydroxy-17a-pregn-4-en-20-yn-3-one in dioxane containing hydrogen chloride. M.P. 196-197 C.(crystallized from acetone/hexane); UV: c =24,400; [a] 67 (c.=0.08 indioxane).

EXAMPLE 14 Preparation of:19-methylene-21-chloro-17-hydroxy-17upregna-4,6-dien-20-yn-3-one Usingthe procedure described in Example 11, 19-methylene-21-chloro-17-hydroxy 17oz pregna-4,6-dien- 20-yn-3-one wasprepared from dichlorodicyanobenzoquinone in dioxane containing hydrogenchloride and 19-methylene-2 l-chloro 17 hydroxy-17u-pregn-4-en-20-yn-3-one in dioxane containing hydrogen chloride. M.P. l37-139 C.(crystallized from acetone/hexane); UV: e :26,100; M 85 (c.=0.1 indioxane).

9 EXAMPLE 15 Preparation of: cis-19-ethylidene-21-chloro-l7-hydroxy-17u-pregna- 1 ,4,6-trien-20-yn-3-one A solution of 1.1 g. ofcis-l9-ethy1idene 21 chloro-17- hydroxy 17a pregna-4,6-dien-20-yn-3-onein 50 ml. of dioxane, containing 0.2% of hydrogen chloride, is reactedwith 0.87 g. of dichlorodicyanobenzoquinone under an argon atmosphereand stirred at room temperature for 24 hours. Sodium bicarbonate (3=g.)is then added and the reaction mixture boiled at reflux for 1 hour. Themixture is cooled after dilution with 50 ml. of benzene and theresultant product is filtered. The filtrate is then further filteredover a 30-fold quantity of aluminum oxide (activity II) and rinsed withacetic acid ester. Evaporation of the extract yielded: cis 19ethylidene-Zl-chlorol7-hydroxy-l7a-pregna 1,4,6, trien-20-yn-3-one. M.P.211-212 C. (crystallized from acetone/hexane); UV: 225= 2s5= ao2= 1589(c.=0.1 in dioxane).

EXAMPLE 16 Preparation of: trans-19-ethylene-21-chloro-17-hydroxy-17a-pregna-1,4,6-trien-20-yn-3-one Using the procedure described inExample 15, trans-19- ethylene-Zl-chloro 17hydroxy-l7a-pregna-1,4,6-trien 20 yn 3-one, was prepared fromdichlorodicyanobenzoquinone and trans-19-ethylidene 21-chloro 17hydroxy- 17x-pregna-4,6-dien 20 yn-3-one in dioxane containing hydrogenchloride. M.P. 242244 C. (crystallized from acetone/ hexane) UV: 13,100;e =8,940; 302=10,- 800; [a] =258 (c.=0.1 in dioxane).

EXAMPLE 17 Preparation ofcis-19-ethylidene-17fi-hydroxy-17-(trifluoro-l-propynyl)-androsta-1,4,6-trien-3-oneUsing the procedure described in Example 15, cis-19- ethylidene 17,8hydroxy 17 (trifiuoro-1-propynyl)- androsta-1,4,6-trien-3-one wasprepared from dichlorodicyanobenzoquinone andcis-19-ethylidene-17,6-hydroxy- 17-(trifiuoro-1-propynyl)androsta-4,6-dien-3-one in dioxane containing hydrogen chloride. M.P.from 260 C. dec. (crystallized from acetone/hexane); UV2e =11,- 140,E:9,200, 302=9,450; [06:]5 =130 (C.=0.1 in oxane).

EXAMPLE '18 Preparation of:l-9-methylene-21-chloro-17-hydroxy-l7apregna-1,4,6-trien-20-yn-3-oneUsing the procedure described in Example 15, 19-methylene-Zl-chloro-17-hydroxy 17oz pregna 1,4, 6- trien-ZO-yn-3-one wasprepared from dichlorodicyanobenzopuinone and 19methylene-2l-chlorol7-hydroxy-l7-apregna-4, 6-dien-2'0-yn-3-one in dioxane containinghydrogen chloride. 'P.M. l59-l-60 C, (crystallized from aceone/hexane);UV: 227=11,850; s =8,730; e =l1,- 500'; [a] =-240.

EXAMPLE 19 Preparation of l9-ethyl-21-chloro-17-hydroxy-17apregna-4,6-dien=20-yn-3-one A solution of 8.92 g. of cis-dichloroethylene in 60ml. of ether to 130 ml. of 1.2 N methyl-lithium solution is addeddropwise over a one hour period and under an argon atmosphere. Thereaction mixture is stirred at room temperature for 2 hours and asolution of 3 g. of 19- ethyl-3-methoxyandrosta-3,5-dien-17-one in 55ml. of ether is added dropwise. The resulting mixture is stirred at roomtemperature for an additional 2 hours, cooled to 'C., decomposed with asaturated ammonium chloride solution and extracted with ether. Theethereal phase is washed with a saturated sodium chloride solution,dried over sodium sulphate and the solvent evaporated. The

EXAMPLE 20 Preparation of:19-ethyl-21-chloro-l7-hydroxy-l7apregna-1,4,6-trien-20-yn-3-one Usingthe procedure described in Example 15, 19-ethyl- 21 chloro-17hydroxy-l7a pregna-1,4,6-trien 20-yn-3- one was prepared fromdichlorodicyanobenzoquinone and 19-ethyl-21 chloro-17 hydroxy-17apregna-4,6-dien- 20-yn-3-one in dioxane containing hydrogen chloride.M.P. 262-265 C. (crystallized from acetone/hexane); [a] =221 (c.=0.1 indioxane).

EXAMPLE 21 Preparation of:19-methyl-2l-chloro-17-hydroxy-17apregna-4-en-20-yn-3-one Using theprocedure secondly described in Example 1, 19-methyl-3methoxyandrosta-3,5 dien-17-one was prepared frorn 2,2-dimethoxypropane,methanol, p-toluenesulfonic acid and l9-methylandrost-4-en-3,17-dione.

Using the procedure first described in Example 1, 19-methyl-21-chloro-17-hydroxy-17a-pregn-4-en-20-yn-3-one was prepared fromcis-dichloroethylene in ether, methyllithium and19-methyl-3-methoxyandrosta-3,S-dien-17-one in ether. M.P. 1 61-l62 C.(crystallized from acetone/ hexane). UV: 242 16,200; [a] =49 (C.=0.1 inoxane).

EXAMPLE '22 Preparation of:19-methyl-21-chloro-17-hydroxy-17apregna-1,4-dien-20-yn-3-one Using theprocedure described in Example 6, 19-methyl-2l chloro-17 hydroxy-l7apregna-l,4 dien-20- yn-3-one was prepared fromdichlorodicyanobenzoquinone and19-methyl-2l-chloro-l7-hydroxy-l7a-pregn-4- en-20-yn-3-one in benzene.M.P. 214-215 C. (crystallized from acetone/hexane); UV: e =15,700; M1 50(c.=0.l in dioxane).

EXAMPLE 23 Preparation of: 19-methyl-21-chloro-l7-hydroxy-17apregna-4,6-dien-20-yn-3-one Using the procedure described in Example 19,19-methyl-2l-chloro-17-hydroxy-l7a-pregna-4,6 dien-20 yn-3- one wasprepared from cis-dichloroethylene, methyllithium and 19methyl-'2-methoxy-androsta-3,S-dien-17- One. 146-147 (3.; UV: 284 23800; [d]5 9= -120 (c.=0.1 in dioxane).

EXAMPLE 24 Preparation of: cis-l9-ethylidene-2l-bromo 17-methoxy-17a-pregn-4-en-20-yn-3-one Using the procedure secondly described inExample 1, cis-1'9 ethylidene-17 hydr-oxy-3 methoxy-lh-pregna-3,5-dien-20-yne is prepared from 2,2-dimethoxypropane, methanol,p-toluenesulfonic acid and cis-19-ethylidene-17-hydroxy-l7a-pregn-4-en-yn-3-one.

1.2 g. of sodium is dissolved in 250 ml. of liquid ammonia containing atrace of iron (III) nitrate and is stirred until the resulting bluecolor disappears. A solution of the enol-ether prepared above, in ml. oftetrahydrofuran is added dropwise at 60 C., and the mixture is stirredfor an additional hour. 20.4 g. of methyl iodide in 25 ml. oftetrahydrofuran is then added followed by stirring for 2% hours. Asaturated ammonium chloride solution (50 ml.) is then added and theammonia evaporated. After extraction, the product was dried yielding:cis-19 ethylidene-3,17 dimethoxy-l7a-pregna-3,S- dien-ZO-yne. Ifdesired, a more pure form of the product can be obtained by splittingthe enol-ether by means of acidic hydrolysis. The resultingcis-l9-ethylidene-l7- methoxy-l7a-pregn-4-en-20-yne-3-one is thencrystallized from acetone/ether and the more pure product is furtherenol etherified.

40 mg. of lithium is added to 40 ml. of dry liquid ammonia containing atrace of iron (III) nitrate. The mixture is stirred until the blue colordisappears. A solution of 370 mg.cis-l9-ethylidene-2,l7-dimethoxy-17a-pregna- 3,5-dien-20-yne in 10 ml.of tetrahydrofuran is added dropwise at 60. The reaction mixture isstirred for one hour and a slow stream of bromotrifluoromethane is thenbubbled through the mixture. 10 ml. of saturated ammonium chloridesolution are then added and the ammonia evaporated. Work-up yields oilycis-19-ethylidene- 21-bromo-3,17-dimethoxy-17a-pregna-3,S-dien-ZO-yne.

The cis 19-ethylidene-2l-bromo-3,17-dimethoxy-17apregna-3,5-dien-20-yneis submitted to acidic hydrolysis in analogy to the procedure describedin Example 1. Chromatography on the 50-fold amount of silica gel usinghexane/acetone (98:2) yields 140 mg. cis-l9-ethylidene- 21 bromo 17methoxy-17a-pregn-4-en-20-yn-3-one, M.P. 101-103".

We claim:

1. A l9-homo-steroid of the formula:

wherein R is selected from the group consisting of a 3- keto-A",3-keto-A 3-keto-A 3-keto-A 3-alkoxy- A 3-alkoxy-A 3-alkoxy-A 3-hydroxy-A3-hydroxy- A, 3-acyloxy-A 3-acyloxy-A 3-acyloxy-A system; R is selectedfrom the group consisting of lower alkyl having at least two carbonatoms and lower alken-l'-yl; R is selected from the group consisting ofhalo-loweralkenyl and halo-lower alkynyl; and R is selected from thegroup consisting of hydroxy, acyloxy and alkoxy, said acyloxy being aresidue of a carboxylic acid selected from the group consisting ofsaturated aliphatic carboxylic acids, aromatic carboxylic acids andunsaturated aliphatic carboxylic acids wherein the carboxylic acidscontain from 2 through 10 carbon atoms and said alkoxy contains from 1through 8 carbon atoms.

2. The compound of claim 1 which is 19-ethyl-21-chloro-17-hydroxy-l7u-pregn-4-en-20-yn-3-one.

3. The compound of claim 1 which is cis-19-ethylidene-21-chloro-17-hydroxy-17a-pregn-4-en-20-yn-3-one.

4. The compound of claim 1 which istrans-19-ethylidene-2l-chloro-17-hydroxy-17 x-pregn-4-en-20-yn-3-one.

5. The compound of claim 1 which is19-methylene-2lchloro-17-hydroxy-17a-pregn-4-en-20-yn-3-one.

6. The compound of claim 1 which is cis-l9-ethylidene- 1 Y Y l7(trifiuoro-l-propynl)-androst-4-en- 3-one.

7. The compound of claim 1 which is cis-19-ethylidene- 21 chloro 17hydroxy-17u-pregna-l,4-dien-20-yn-3- one.

8. The compound of claim 1 which is trans-19-ethylidene 21 chlorol7-hydroxy-17a-pregna-l,4-dien-20 yn-3-one.

9. The compound of claim 1 which is 19-methylene-21-chloro-17-hydroxy-17a-pregna-l,4-dien-20-yn-3-one.

10. The compound of claim 1 which is l9-ethyl-21-chl0ro-17-hydroxy-17u-pregna-1,4-dien-20-yn-3-one.

11. The compound of claim 1 which is cis-19-ethylidene 17 5 hydroxy-17-(trifiuoro-1-propynyl)-androsta- 1,4-dien-3-one.

12. The compound of claim 1 which is cis-19-ethylidene 21chloro-17-hydroxy-17a-pregna-4,6-dien-20 yn-3-one.

13. The compound of claim 1 which is cis-19-ethylidene 1718hydroxy-17-(trifluoro-1-propynyl)-androsta- 4,6-dien-3-one.

14. The compound of claim 1 which is trans-19-ethylidene 21 chloro17-hydroxy-17a-pregna-4,6-dien-20 yn-3-one.

15. The compound of claim 1 which is 19-methylene-2l-chloro-17-hydroxy-17a-pregna-4,6-dien-20-yn-3-one.

16. The compound of claim 1 which is cis-19-ethylidene 21 chloro17-hydroXy-17u-pregna-1,4,6-trien- 20-yn-3-one.

17. The compound of claim 1 which is trans-19-ethylidene 21 chloro17-hydroxy-17a-pregna-1,4,6-trien- 20-yn-3-one.

18. The compound of claim 1 which is cis-19-ethylidene 17Bhydroxy-I7-(triiiuoro-l-propynyl)-androsta- 1,4,6-trien-3-one.

19. The compound of claim 1 which is 19-methylene-21-chloro-17-hydroxy-l7a-pregna-1,4,6-trien-20-yn-3 -one.

20. The compound of claim 1 which is 19-ethyl-21-chloro-17-hydroxy-17a-pregna-4,6-dien-20-yn-3-one.

21. The compound of claim 1 which is 19-ethyl-21-chloro-17-hydroxy-l7u-pregna-1,4,6-trien-20-yn-3-one.

22. The compound of claim 1 which isl9-methyl-2lchloro-17-hydroxy-17a-pregn-4-en-20-yn-3-one.

23. The compound of claim 1 which is 19-methyl-21-chloro-17-hydroxy-17u-pregna-1,4-dien-20-yn-3-one.

24. The compound of claim 1 which is 19-methyl-21-chloro-17-hydroxy-17ec-pregna-4,6-dien-20-yn-3-one.

25. The compound of claim 1 which iscis-19ethylidene-17-hydroxy-17a-pregn-4-en-20-yn-3-one.

References Cited UNITED STATES PATENTS 3,141,025 7/1964 Nomine et a1260-3409 3,275,622 9/1966 Bowers 260-23955 3,309,387 3/1967 Furst et a1260-3975 HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

